The long-term goal of this study is to identify genes and biologic pathways related to inflammation that influence the rapid decline in function and influence frailty and mortality in a subset of older adults. Inappropriate activation of the pro-inflammatory protein NFkB acts as an important gateway in this process. We have identified a cluster of inflammatory mediators that are related to NFkB and that predict poor health outcomes. We hypothesize that this cluster of cytokines represents a pro-inflammatory phenotype, and that variation in genes that trigger or propagate NFkB activity contributes to the pro-inflammatory state and hence to the poor health comes observed in some older adults. We propose here to further refine the inflammatory phenotype in the In Chianti population of older adults, followed by a validation step in which we will measure the most important contributors to this phenotype in stored serum from the Cardiovascular Health Study and determine if these markers are related to the same poor health outcomes. We will then identify potentially meaningful gene variants within NFkB related candidate genes in a case control study of CHS participants, and determine if any of these polymorphisms, or combination of these polymorphisms influence inflammation and poor health outcomes. Finally, we will pick the most influential candidate genes determined in the CHS study, and test them in the entire CHS population and in In CHIANTI and determine if these genes are predictive of the same poor health care outcomes. Clinically meaningful genotypes will highlight potential biologic pathways for interventions into a range of poor health outcomes in older adults.